STORY BY

Scott Merville

Some people smoke, eat unhealthily, shun exercise, yet manage to avoid the damaged arteries that are often the price of such a lifestyle. A built-in protective mechanism in the smooth muscle cells of the blood vessels discovered by University of Texas Health Science Center at Houston researchers may explain their good fortune.

A protein known to play a critical role in preventing cancer also is the driving force of a “growthostat” that limits the proliferation of vascular smooth muscle cells in a timely and surprising way, says Ken Fujise, M.D., associate professor of cardiology at UT Medical School and a researcher at the UT Institute of Molecular Medicine for the Prevention of Human Diseases (IMM).

“Smooth muscle cells add integrity and strength to the blood vessel wall. In the human body, these cells also are quiescent, or asleep—they do not grow,” Fujise explains. And for a very good reason: smooth muscle cell overgrowth would block the arteries.

A variety of stimuli can set these cells off on a dangerous growth spurt. Cholesterol and smoking will do it, as will diabetes, for example, Fujise says. When smooth vessel cells grow, they join with the fatty plaques caused by cholesterol to cause atherosclerosis, the hardening, thickening and stiffening of the blood vessel walls that can lead to heart attack or stroke. Cholesterol alone, Fujise notes, explains only about half of all atherosclerotic disease.

Protein p53: The Plot Thickens

Enter the tumor suppressor protein p53. Well established as a critical player in eliminating cancer cells, research also connects the absence or suppression of p53 to atherosclerosis and restenosis, the re-blockage of blood vessels that have been cleared via angioplasty. Mice that lack p53 develop more severe atherosclerosis, for example.

“So, we have suspected that p53 is important in protecting against atherosclerosis, but we didn’t know how it worked. What our lab has shown is what we believe is the mechanism by which p53 works,” Fujise says. The team recently described its findings in Circulation: Journal of the American Heart Association.

The research team stimulated the growth of human aortic vascular smooth muscle cells in the laboratory by exposing them to blood serum that contained large amounts of known growth factors. This process mimics atherosclerotic stimulation in the body, Fujise explains.

As expected, the smooth muscle cells divided and reproduced. Lab tests then showed a surprising development: As the cells grew, they began to produce p53. In turn, the newly “upregulated” protein put the brakes on cell growth.

Powerful Proteins

It did this by activating two genes that, in turn, produce a pair of anti-growth proteins, Fujise’s research shows. One protein disrupts the cell growth cycle, arresting the process of cell division and forcing the cell back to its original state. The other induces cells to commit suicide, a process called apoptosis.

About 30 percent of the aortic vascular smooth muscle cells produced p53, Fujise says. The result was a mosaic of cells in the walls of blood vessels that had undergone vascular smooth muscle cell growth. Some cells were growing, others were in their original state, and some were dead – apoptotic, Fujise says.

As it happens, this mosaic is exactly what has been observed in clinical studies of vascular tissue that has undergone restenosis – a renewed blockage of the blood vessel after it has been opened once by balloon angioplasty or a stent. “So what we have is a strong connection between basic science in the lab and an important clinical observation,” Fujise says, an observation that previously had been considered a mystery.

“The evidence shows that p53 is the key factor in regulating vascular smooth muscle cell growth. It works like a thermostat – we call it a growthostat -- in the smooth muscle cell, so those cells can multiply, but not limitlessly.”

If You’ve Got the Gene, You’re Lucky

The p53 gene is one of the most variable in the human genome. Fujise believes variation in the gene could have a major impact on a person’s susceptibility to cardiovascular disease. “If your genes are capable of producing lots of p53 in response to stimuli, you are protected. If they activate late or minimally, you’re in trouble.”

That smoker who avoids atherosclerosis could have a version of p53 that springs quickly and vigorously into action to limit cell growth stimulated by his tobacco use.

Fujise plans to connect with a geneticist to conduct a clinical trial comparing variation in p53 and incidence of cardiovascular disease. Greater understanding of the genetic connection and molecular switches that trigger the p53 response could lead to medical treatments that boost protection against atherosclerosis.

Last Updated: 9-23-2003

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